ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Ondexxya 200 mg powder for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 200 mg of andexanet alfa*. After reconstitution, each mL of solution contains 10 mg of andexanet alfa.

* Andexanet alfa is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Powder for solution for infusion White to off-white lyophilized powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indications For adult patients treated with a direct factor Xa (FXa) inhibitor ( or ) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. 4.2 Posology and method of administration Restricted to hospital use only. Posology Andexanet alfa is administered as an intravenous bolus at a target rate of approximately 30 mg/min over 15 minutes (low dose) or 30 minutes (high dose), followed by administration of a continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes (see table 1). Table 1: Dosing regimens Initial Continuous Total number intravenous intravenous of 200 mg bolus infusion vials needed Low dose 400 mg at a target rate of 4 mg/min for 120 minutes 5 30 mg/min (480 mg) High dose 800 mg at a target rate of 8 mg/min for 120 minutes 9 30 mg/min (960 mg)

Reversal of apixaban The recommended dose regimen of Ondexxya is based on the dose of apixaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of apixaban (see table 2).

2 Table 2: Summary of dosing for reversal of apixaban

Timing of last dose before Ondexxya initiation FXa inhibitor Last dose < 8 hours or unknown ≥ 8 hours

≤ 5 mg Low dose

Apixaban > 5 mg/ High dose Low dose Unknown

Reversal of rivaroxaban The recommended dose regimen of Ondexxya is based on the dose of rivaroxaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of rivaroxaban (see table 3). Table 3: Summary of dosing for reversal of rivaroxaban

Timing of last dose before Ondexxya initiation FXa inhibitor Last dose < 8 hours or unknown ≥ 8 hours

≤ 10 mg Low dose

Rivaroxaban > 10 mg/ High dose Low dose Unknown

Restarting antithrombotic therapy Following administration of Ondexxya and cessation of a major bleed, re-anticoagulation should be considered to prevent thrombotic events due to the patient’s underlying medical condition. Antithrombotic therapy can be re-initiated as soon as medically indicated following treatment if the patient is clinically stable and adequate haemostasis has been achieved. Medical judgement should balance the benefits of anticoagulation with the risks of re-bleeding (see section 4.4). Special populations Elderly patients (aged 65 years and over): No dose adjustment is required in elderly patients (see section 5.2). Renal impairment: The effect of renal impairment on andexanet alfa exposure levels has not been evaluated. Based on the existing data on clearance, no dose adjustment is recommended. Hepatic impairment: Based on the existing data on clearance of andexanet alfa, no dose adjustment is recommended. The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2). Paediatric population: The safety and efficacy of andexanet alfa in children and adolescents have not been established. No data are available.

Method of administration

Intravenous use After an appropriate number of vials of Ondexxya has been reconstituted, the reconstituted solution (10 mg/mL) without further dilution is transferred to sterile large volume syringes in case a syringe

3 pump is used for administration or to suitable empty intravenous bags comprised of polyolefin (PO) or polyvinyl chloride (PVC) material (see section 6.6). Prior to administration by IV infusion a 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein- binding filter should be used.

Ondexxya is administered as an IV bolus at a target rate of approximately 30 mg/min over 15 to 30 minutes, followed by administration of a continuous infusion of 4 mg (low dose) or 8 mg (high dose) per minute for 120 minutes (see table 1).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications Hypersensitivity to the active substance or to any other ingredients listed in section 6.1.

Known allergic reaction to hamster proteins.

4.4 Special warnings and precautions for use

Limitations of use Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers dosed with apixaban or rivaroxaban. Andexanet alfa is not suitable for pre-treatment of urgent surgery. Use for - or enoxaparin-reversal is not recommended due to lack of data. Andexanet alfa will not reverse the effects of non-FXa inhibitors (see section 5.1).

Treatment monitoring should be based mainly on clinical parameters indicative of appropriate response (i.e., achievement of haemostasis), lack of efficacy (i.e., re-bleeding), and adverse events (i.e., thromboembolic events). Treatment monitoring of andexanet alfa should not be based on anti- FXa-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa as these assays result in erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa.

Dosage recommendation is based upon data-modelling in healthy volunteers. Validation has not been successful, yet. Data from bleeding patients are limited. Preliminary data suggest higher risk of thrombosis for patients receiving the higher dose of andexanet, previous lower dose of the anti- FXa inhibitor, and patients on rivaroxaban.

In ANNEXA-4, intracranial haemorrhage (ICH) patients (GCS > 7 and haematoma volume < 60 mL) have been included. Treatment of patients with more severe ICH with andexanet alfa has not been studied.

Thrombotic events Thrombotic events have been reported following treatment with andexanet alfa (see sections 4.8 and 5.1). Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thrombotic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. In addition, independent pro-coagulant effect of andexanet alfa, mediated by inhibition of tissue factor pathway inhibitor (TFPI), has been demonstrated, which may pose a risk of developing thrombosis. Duration of this effect in bleeding patients is not known. Laboratory parameters as anti- FXa activity, endogenous thrombotic potential (ETP), or markers of thrombosis might not be reliable for guidance. To reduce this risk, resumption of therapy should be considered as soon as medically appropriate after completion of treatment.

In healthy volunteers, dose-dependent increases in coagulation markers F1+2, TAT, and D-dimer, and dose-dependent decreases in TFPI, after administration of andexanet alfa were observed, but no

4 thromboembolic events were reported. These markers were not measured in patients enrolled in the ANNEXA-4 study, but thromboembolic events have been observed (see section 5.1). Monitoring for signs and symptoms of thrombosis is, therefore, strongly recommended.

Use of andexanet alfa in conjunction with other supportive measures Andexanet alfa can be used in conjunction with standard haemostatic supportive measures, which should be considered as medically appropriate.

The safety of andexanet alfa has not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood within seven days prior to the bleeding event, as they were excluded from clinical trials. Pro-coagulant factor treatments (e.g., 3- or 4- factor prothrombin complex concentrate (PCC)/activated PCC, recombinant factor VIIa, fresh frozen plasma) and whole blood should be avoided unless absolutely required, due to lack of data in combination with these treatments.

Interaction with Use of andexanet prior to heparinization e.g. during surgery should be avoided as andexanet causes unresponsiveness to heparin. Use of andexanet as an for heparin or low-molecular weight heparin has not been evaluated and is not recommended (refer to Section 4.5.).

Infusion-related reactions In case of mild or moderate infusion reactions, careful observation may be sufficient. For moderate symptoms, consideration may be given to a brief interruption or slowing of the infusion with resumption of the infusion after symptoms subside. Diphenhydramine may be administered.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies with andexanet alfa have been performed.

In vitro data suggest interaction of andexanet alfa with the heparin- anti- III (ATIII) complex and neutralization of the anticoagulant effect of heparin. Off-label use of andexanet alfa pre-surgery with intended heparin-anticoagulation has been reported to cause unresponsiveness to heparin (refer to Section 4.4). Use of andexanet as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy There are no data from the use of andexanet alfa in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Andexanet alfa is not recommended during pregnancy or in women of childbearing potential not using contraception.

Breast-feeding It is unknown whether andexanet alfa is excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with andexanet alfa.

Fertility There are no data on the effects of andexanet alfa on human fertility.

4.7 Effects on ability to drive and use machines

Andexanet alfa has no or negligible influence on the ability to drive and use machines.

5 4.8 Undesirable effects

Summary of the safety profile The safety has been evaluated in clinical trials including 247 healthy subjects administered an FXa inhibitor, as well as in 352 patients in a Phase IIIb/IV trial (ANNEXA-4), who had acute major bleeding and were under treatment with an FXa inhibitor (mostly apixaban and rivaroxaban).

In the clinical trials in healthy subjects administered an FXa inhibitor and then receiving andexanet alfa, no serious or severe adverse reactions were reported. The most frequently observed adverse reactions were mild or moderate infusion-related reactions (see table 4) comprising symptoms such as flushing, feeling hot, cough, dysgeusia, and dyspnoea occurring within a few minutes to a few hours of the infusion. Among the healthy subjects studied, women experienced more adverse reactions (mainly infusion-related reactions) than men.

In the healthy subject trials, elevations > 2 x ULN in D-dimer and prothrombin fragments F1+2 were frequently observed. These elevations were maintained between several hours to a few days following administration, but no thrombotic events were reported. Clinical relevance in the target population (patients with uncontrolled or life-threatening bleeding who are anticoagulated due to high to very high risk of thrombosis) is unknown.

Tabulated list of adverse reactions Table 4 provides the list of adverse reactions from clinical studies of healthy subjects treated with andexanet alfa. The second column provides the list of adverse reactions from the interim results of the Phase IIIb/IV ANNEXA-4 study, including 352 patients with acute major bleeding treated with andexanet alfa. The adverse reactions are classified by system organ class (SOC) and frequency, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); or not known (cannot be estimated from available data).

Table 4: List of adverse reactions in healthy subjects and bleeding patients

System organ class/ Frequency in Frequency in Preferred term healthy bleeding volunteers patients Immune system disorders Urticaria common Nervous system disorders Cerebral infarction uncommon Cerebrovascular accident uncommon Dizziness postural common Headache common Ischaemic common Transient ischaemic attack uncommon Cardiac disorders Acute uncommon uncommon Myocardial infarction uncommon Palpitations common Vascular disorders

6 Deep vein thrombosis uncommon Iliac artery occlusion uncommon Respiratory, thoracic and mediastinal disorders Cough common Dyspnoea common Pulmonary embolism uncommon

7

System organ class/ Frequency in Frequency in Preferred term healthy bleeding volunteers patients Gastrointestinal disorders Abdominal discomfort common Abdominal pain common Dry mouth common Dysgeusia common Nausea common Skin and subcutaneous tissue disorders Pruritus common Pruritus generalised common Musculoskeletal and connective tissue disorders Back pain common Muscle spasms common General disorders and administrative site conditions Flushing very common Feeling hot very common Chest discomfort common Hyperhidrosis common Peripheral coldness common Pyrexia common Investigations Transient elevations of D-dimer and F1+2 fragments very common

Description of selected adverse reactions Based on data from 352 patients from the Phase IIIb/IV ANNEXA-4 study treated with an FXa inhibitor and experiencing an acute major bleeding episode, one patient experienced a serious or severe infusion-related reaction. Thirty-six of 352 patients with complete 30-day safety follow up (10.3%) had thrombotic events, including venous thromboembolism (VTE), myocardial infarction (MI), and stroke. Ten of 36 (27.8%) patients had restarted antithrombotic therapy at the time of the event, and all 36 patients had been anticoagulated for a prior history of VTE and/or atrial fibrillation at the time of receiving andexanet alfa (see sections 4.4 and 5.1).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important, as it allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose There is no clinical experience with overdose of andexanet alfa. No dose-limiting toxicities have been observed during clinical trials.

8 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: All other therapeutic products, . ATC code: V03AB38 Mechanism of action Andexanet alfa is a recombinant form of human FXa protein that has been modified to lack FXa enzymatic activity. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin, and the gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the ability of the protein to assemble into the prothrombinase complex, thus removing any anti-coagulant effects. Andexanet alfa is a specific reversal agent for FXa inhibitors. The predominant mechanism of action is the binding and sequestration of the FXa inhibitor. In addition, andexanet alfa has been observed to bind to, and inhibit tissue factor pathway inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor-initiated thrombin generation inducing a pro-coagulant effect. Pharmacodynamic effects The effects of andexanet alfa can be measured through pharmacodynamic markers, including free fraction of available FXa inhibitor as well as through restoration of thrombin generation. In addition, andexanet alfa has been shown to inhibit TFPI-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa. Due to the reversible binding of andexanet alfa to the FXa inhibitor, the high sample dilution currently used in these assays leads to dissociation of the inhibitor from andexanet alfa, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa. In prospective, randomized, placebo-controlled, dose-ranging studies in healthy subjects, the dose and dose regimen of andexanet alfa required to reverse anti-FXa activity and restore thrombin generation for FXa inhibitors (apixaban or rivaroxaban) were determined with modified assays that are not commercially available. The maximal reversal of anti-FXa activity was achieved within two minutes of completing the bolus administration. Administration of andexanet alfa as a bolus followed by continuous infusion resulted in a sustained decrease in anti-FXa activity. The anti-FXa activity returned to the placebo levels and above approximately two hours after the end of a bolus or infusion dependent on dosage. When andexanet alfa was administered as a bolus followed by a continuous infusion, the maximum decrease in unbound FXa inhibitors was rapid (within two minutes of the end of the bolus) and was sustained over the course of the infusion then gradually increased over time, reaching a maximum at approximately two hours following the end of infusion. Restoration of thrombin generation following administration was dose- and dose-regimen- dependent and did not correlate with anti-FXa-activity beyond approximately four hours (see below, “restoration of thrombin generation”). Plasma TFPI activity has been shown to be inhibited completely from 2 minutes to 14.5 hours after andexanet alfa bolus-administration, and returned to baseline within 3 days. Tissue-factor (TF)-initiated thrombin generation immediately increased above the baseline (prior to anticoagulation) and remained elevated for > 20 hours in contrast to placebo. Plausibility of a pro- coagulant effect of TFPI-inhibition is supported by consecutive and sustained slopes of D-Dimers, TAT, and F1+2.

PK/PD modelling Bolus strengths of andexanet alfa being necessary to achieve mean unbound apixaban (400 mg bolus) and unbound rivaroxaban concentrations (800 mg bolus) below the anticipated respective threshold for no anticoagulant effect were twice as high for rivaroxaban (20 mg QD) compared to apixaban (5 mg BID), due to the differential PK characteristics and dose levels of respective FXa inhibitor.

9 Clinical efficacy and safety The efficacy and safety of andexanet alfa have been evaluated in the following: 1) randomized, placebo-controlled, Phase II dose-ranging trials with healthy volunteers administered FXa inhibitors to establish doses required for reversal; 2) two Phase III studies, one with apixaban and the other with rivaroxaban, to confirm the efficacy of the high and low dose regimens; and 3) a global, multicentre, prospectively defined, open-label Phase IIIb/IV study (ANNEXA-4) in patients with an acute major bleeding episode requiring urgent reversal of FXa anticoagulation.

Reversal of anticoagulation in healthy subjects aged 50-75 (Studies 14-503 and 14-504) In a prospective, randomized, placebo-controlled study, healthy subjects with a median age of 56.5 years on apixaban 5 mg twice daily received andexanet alfa (n=24) administered as a 400 mg IV bolus immediately followed by a 4 mg per minute IV infusion for 120 minutes (480 mg) or placebo (n=8).

In a similar study, subjects with a median age of 57 years on rivaroxaban 20 mg daily received andexanet alfa (n=26) administered as an 800 mg IV bolus immediately followed by an 8 mg per minute IV infusion for 120 minutes (960 mg) or placebo (n=13).

Reduction in anti-FXa activity The primary endpoint for both Study 14-503 (apixaban) and Study 14-504 (rivaroxaban) was the percent change in anti-FXa activity from baseline to post-infusion nadir.

Among the apixaban-treated subjects in Study 14-503, the percent change in anti-FXa activity was -92.34% (± 2.809%) for the andexanet alfa group and -32.70% (± 5.578%) for the placebo group (p < 0.0001), the latter reflecting the intrinsic clearance of the anticoagulant.

Among the rivaroxaban-treated subjects in Study 14-504, the percent change in anti-FXa activity was -96.72% (± 1.838%) for the andexanet alfa group and -44.75% (± 11.749%) for the placebo group (p < 0.0001), the latter reflecting the intrinsic clearance of the anticoagulant.

The time courses of anti-FXa activity before and after andexanet alfa administration are shown in Figure 1. Reduction in anti-FXa activity correlates with restoration of thrombin generation. The anti- FXa activity thresholds for normalization of thrombin generation (defined by mean ETP and standard deviations) were estimated to be 44.2 ng/mL (within one standard deviation of normal ETP) based on pooled data from Studies 14-503 and 14-504, as indicated in the figure.

Figure 1: Change in anti-FXa activity (ng/mL) in healthy subjects anticoagulated with apixaban (A) and rivaroxaban (B)

(A)

10

(B)

Restoration of thrombin generation In both, Study 14-503 and Study 14-504, treatment with andexanet alfa also resulted in a statistically significant increase in thrombin generation in healthy subjects anticoagulated with apixaban or rivaroxaban versus placebo (p < 0.0001). Restoration of thrombin generation to within normal ranges (defined as one standard deviation from baseline levels) within two minutes and maintained for 20 hours was achieved with bolus only and bolus plus infusion for low-dose andexanet alfa in subjects on apixaban. For subjects on rivaroxaban, high-dose andexanet alfa (bolus plus infusion) resulted in increased thrombin generation above two standard deviations. No clinical evaluation for apixaban- treated subjects with high-dose andexanet alfa and no evaluation for rivaroxaban-treated subjects with low-dose andexanet alfa was performed in these studies.

Change from baseline in free FXa inhibitor concentration at nadir The mean unbound concentrations of apixaban and rivaroxaban were < 3.5 ng/mL and 4 ng/mL, respectively, after bolus andexanet alfa administration and were maintained throughout the continuous infusion. These levels of unbound FXa inhibitor provide little or no anticoagulant effect.

Reversal of FXa inhibitor anticoagulation in patients with acute major bleeding In Study 14-505 (ANNEXA-4), a Phase IIIb/IV multinational, prospective, single-arm, open-label study, Ondexxya was administered to 352 patients on FXa inhibitors who presented with acute major bleeding. The two co-primary endpoints are: a) percent change in anti-FXa activity from baseline to the nadir between five minutes after the end of the bolus until the end of the infusion, and; b) rate of good or excellent (compared to poor or none) haemostatic efficacy within 12 hours after infusion, as rated by an independent endpoint adjudication committee.

In an updated interim analysis, data of 352 patients were evaluated.

Approximately half of the patients were male, and the mean age was 77.4 years. Most patients had previously received either apixaban (194/352; 55.1%) or rivaroxaban (128/352; 36.4%), and experienced either an ICH (230/352; 65.3%) or a gastrointestinal (GI) bleed (94/352; 26.7%). 297/352 Patients (84.4%) received the low-dose regimen of andexanet, while 55 patients (15.6%) received the high-dose regimen.

Of 352 enrolled patients, 249 (70.7%) were included in the efficacy-analysis. For these patients, median anti-FXa activity at baseline was 149.7 ng/mL for patients taking apixaban, and 211.8 ng/mL for patients taking rivaroxaban. Median change from baseline to nadir in anti-FXa activity was -93.4% (95% CI -94.3%, -92.4%) for apixaban, and -92.5% (95% CI -94.2%, -90.3%) for rivaroxaban.

Haemostatic efficacy was good or excellent in 81.9% of 249 patients.

The updated interim analysis demonstrated that the change in anti-FXa activity (surrogate) was not

11 predictive for achievement of hemostatic efficacy in the overall patient population.

Deaths In the ANNEXA-4 study, of the patients in the safety population completing 30-day follow up (N=351), 54 patients (15.4%) died. The 30-day mortality rates were 16.2% (37/229) in patients presenting with ICH, 12.8% (12/94) with GI bleeding, and 17.9% (5/28) with other types of bleeding. The 30-day mortality rates were 20.1% (44/219) in patients aged > 75 years old and 7.6% (10/132) in patients aged ≤ 75 years. According to region, death rates were 22.1% (31/140) in patients recruited in the European Union and 10.9% (23/211) in patients recruited in North America. Compared with patients recruited in North America, EU patients were significantly older (79.0 years vs. 76.3 years), more frequently had ICH as index event (72.9% vs. 59.0%) and more ICHs were intraparenchymal (54.9% vs. 34.4%). Cardiovascular causes of death (n=27) included: haemorrhagic stroke (n=6), ischaemic stroke (n=5), sudden cardiac death (including unwitnessed) (n=5), cardiomechanical/pump failure (n=4), myocardial infarction (n=2), bleeding other than haemorrhagic stroke (n=1), and other cardiovascular causes (n=4). Non-cardiovascular deaths (n=27) included: respiratory failure (n=5), infection/sepsis (n=5), accident/trauma (n=2), cancer (n=1), and other/non-vascular cause (n=14).

Thromboembolic events In the ANNEXA-4 study, 36 (10.3%) patients experienced a total of 42 thromboembolic events: cerebrovascular accident (CVA) (15/42; 35.7%), deep venous thrombosis (13/42; 33.1%), acute myocardial infarction (8/42; 19.0%), pulmonary embolism (5/42; 11.9%), and transient ischaemic attack (1/42; 2.4%). The median time to event was nine days. A total of 33.3% of patients with thromboembolic events (12/36) experienced the thromboembolic event during the first three days. Of the 209 patients who were re-anticoagulated prior to a thrombotic event, 10 (4.8%) patients experienced a thromboembolic event. At the time of the event 10/36 (27.8%) patients were on antithrombotic therapy. The occurrence of thromboembolic events was generally comparable between patients > 75 years (11.0%; 24/219) and those ≤ 75 years of age (9.1%; 12/132).

No thromboembolic events were observed in 223 healthy volunteers who received FXa inhibitors and were treated with andexanet alfa. Dose-dependent increases in coagulation markers F1+2, TAT, and D-dimers after administration of andexanet alfa were observed, but these markers were not measured in patients enrolled in the ANNEXA-4 study, and their relevance in bleeding patients is not known.

Immunogenicity 345 andexanet alfa-treated healthy subjects were tested for antibodies cross reacting with andexanet alfa and antibodies to and FXa. Treatment-emergent, non-neutralizing antibodies to andexanet alfa were detected in approximately 10% (35/345). These antibodies were generally low titre, and no clinical consequences were observed. No neutralising antibodies or antibodies to factor X or FXa were detected. To date, the occurrence of positive, non-neutralizing antibodies to andexanet alfa following treatment in patients in the ANNEXA-4 study (8.5% or 20/236 patients) has been similar to that observed in healthy subjects.

Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with andexanet alfa in one or more subsets of the paediatric population in treatment and prevention of FXa inhibitor-associated haemorrhages (see section 4.2 for information on paediatric use).

Conditional approval This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year, and this SmPC will be updated as necessary.

12 5.2 Pharmacokinetic properties

Studies of andexanet alfa in the presence of direct FXa inhibitors in healthy subjects demonstrated dose proportional pharmacokinetics over the intended therapeutic dose range evaluated for both Cmax and area under the curve (AUC). FXa inhibitors did not affect andexanet alfa pharmacokinetics at therapeutic levels. Table 5. Pharmacokinetic parameters for Andexanet bolus-injection of 400 and 800mg

PK Parameter 400 mg Bolus 800 mg Bolus 61.3 127 AUC0-∞ (hr*µg/mL) [43.8, 94.9] [57.5, 209] 61.0 118 Cmax (µg/mL) [40.3, 98.5] [50.2, 191] 6.52 6.29 Clearance (L/hr) [4.21, 9.13] [3.83, 13.9] 3.78 4.24 T1/2 (hr) [2.59, 6.39] [2.47, 6.52] 9.47 8.94 Vss (L) [6.08, 15.3] [5.36, 23.1] Source : Study 19-514 Data presented are geometric mean [min, max]

Pharmacokinetics in special populations

Elderly population In a study comparing andexanet alfa pharmacokinetics in elderly (65-69 years) and younger (26-42 years) healthy subjects who had received apixaban, the pharmacokinetics of andexanet alfa in the elderly subjects were not statistically different than those in the younger subjects.

Renal impairment No trials have been conducted to investigate the pharmacokinetics of andexanet alfa in renally impaired patients. Based on the available PK data, andexanet alfa has little to no renal clearance, and thus would not require dose adjustment for patients with renal impairment.

Hepatic impairment No trials have been conducted to investigate the pharmacokinetics of andexanet alfa in patients with hepatic impairment. Biliary and/or faeces elimination of protein therapeutics is not a known route of protein elimination. Therefore, dose adjustment is not considered needed for patients with hepatic impairment.

Gender Based on population pharmacokinetics analysis, gender does not have a clinically meaningful effect on the pharmacokinetics of andexanet alfa.

Paediatric population The pharmacokinetics of andexanet alfa has not been studied in paediatric patients.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity studies up to two weeks in rats and monkeys. Studies to evaluate the mutagenic and carcinogenic potential of andexanet alfa have not been performed. Based on its mechanism of action and on the characteristics of proteins, no carcinogenic or genotoxic effects are anticipated. Animal reproductive and developmental studies have not been conducted with andexanet alfa.

13 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tris base Tris hydrochloride L-arginine hydrochloride Sucrose Mannitol Polysorbate 80

6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life Vial (unopened) Three years stored at 2°C to 8°C. Reconstituted medicinal product Chemical and physical in-use stability has been demonstrated for 16 hours at 2°C to 8°C in the primary packaging vial. If needed, the reconstituted solution once transferred into the IV bag can be stored for an additional eight hours at room temperature. From a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage Store in a refrigerator (2°C to 8°C). Do not freeze. For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container Powder in a 20 mL vial (Type I glass) with a stopper (butyl rubber). Pack size of four vials.

6.6 Special precautions for disposal and other handling Reconstitution The following are needed before starting reconstitution: • Calculated number of vials (see section 4.2). • Same number of 20 mL (or larger) solvent syringes equipped with a 20 gauge (or larger) needle. • swabs. • Large (50 mL or larger) sterile syringe. If a syringe pump is used for administration, multiple syringes should be used to contain the final volume of reconstituted product. • Intravenous bags of polyolefin (PO) or polyvinyl chloride (PVC) material (150 mL or larger) to contain the final volume of reconstituted product (if administration is performed with IV bags). • Water for injections. • 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter.

Andexanet alfa does not need to be brought to room temperature before reconstitution or administration to the patient. Aseptic technique during the reconstitution procedure should be used. Each vial is reconstituted according to the following instructions:

14 1. Remove the flip-top from each vial. 2. Wipe the rubber stopper of each vial with an alcohol swab. 3. Using a 20 mL (or larger) syringe and a 20 gauge (or larger) needle, withdraw 20 mL of water for injections. 4. Insert the syringe needle through the centre of the rubber stopper. 5. Push the plunger down to slowly inject the 20 mL of water for injections into the vial, directing the stream toward the inside wall of the vial to minimise foaming. 6. Gently swirl each vial, until all of the powder is completely dissolved. DO NOT SHAKE the vials, as this can lead to foaming. The dissolution time for each vial is approximately three to five minutes. 7. The reconstituted solution should be inspected for particulate matter and/or discolouration prior to administration. Do not use if opaque particles or discolouration are present. 8. For the most efficient reconstitution of the needed dose, and to minimise errors, inject each vial needed with 20 mL of water for injections before proceeding to the next step. 9. Use within eight hours after reconstitution when stored at room temperature.

Administration using a syringe pump 1. Once all required vials are reconstituted, the reconstituted solution is withdrawn from each vial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger) needle. 2. The bolus and infusion are prepared in separate large volume syringes. 3. Due to the additional volume, the high dose bolus and infusion have to be further separated into additional syringes (two syringes apiece for bolus and infusion). 4. To prevent the inadvertent transfer of air, be careful to hold the syringe needle up, and do not set the syringe down between multiple withdrawals from vials. 5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter, syringe pump) in preparation for administration. 6. Administer the reconstituted solution at the appropriate rate. 7. Discard all used syringes, needles, and vials, including any unused portion of reconstituted solution.

Administration using intravenous bags 1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger) needle. 2. Transfer the reconstituted solution from the syringe into an appropriate IV bag. 3. Repeat steps 1 and 2 as necessary to transfer the complete volume of the bolus and the infusion into a PO or PVC IV bags. 4. It is recommended that the bolus and infusion be split into two separate bags to ensure the correct administration rate. Although it is also permissible to use one PO or PVC IV bag for the bolus and infusion, the correct infusion rate must be ensured when switching from the bolus to the infusion. 5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter, IV pump) in preparation for administration. 6. Administer the reconstituted solution at the appropriate rate.

Disposal All used syringes, needles, and vials, including any unused portion of reconstituted solution, should be disposed of in accordance with local requirements.

15 7. MARKETING AUTHORISATION HOLDER

Alexion Europe SAS 103-105 rue Anatole France 92300 Levallois-Perret France

8. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1345/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 26 April 2019 Date of latest renewal: 30 April 2021

10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

16

ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION

17 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Lonza Biologics Porrino, S.L. C/ La Relba s/n Porrino Pontevedra 36410 Spain

Name and address of the manufacturer responsible for batch release

Alexion Pharma International Operations Unlimited Company Alexion Dublin Manufacturing Facility College Business and Technology Park Blanchardstown Rd North Dublin D15 R925 Ireland

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION • Periodic safety update reports The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT • Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted: • At the request of the European Medicines Agency; • Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

18 E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION

This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures:

Description Due date In order to further substantiate correlation of the biomarker (antiFXa-activity) with Submission of haemostatic efficacy and clarify the risk of thromboses and thromboembolic events, the the final CSR MAH should submit the results of ANNEXA-4, an interventional non-randomized, by 30 June multicentre, prospective, open-label, single-group study in patients with acute major 2021 bleeding. In order to confirm posology of Ondexxya, the MAH should provide PK/PD-models, Submission by covering all available PK and PD data in (1st) healthy volunteers and (2nd) target patient 30 June 2022 population. Approved posology should be confirmed by respective simulations. In order to substantiate correlation of the biomarker (antiFXa-activity) with haemostatic Submission of efficacy and clarify the risk of thromboses and thromboembolic events, the MAH the final CSR should submit the results of a global randomised controlled to investigate by 30 June the use of andexanet versus standard of care treatment in patients with intracranial 2023 haemorrhage (ICH) taking apixaban, rivaroxaban, or edoxaban (study 18-513). In order to further confirm the efficacy and safety, the MAH should submit an updated Submission by PK/PD model using all previously incorporated data (from studies 11-501, 12-502, 14- 30 September 503, 14-504, and 14-506) as well as newly incorporated data from study 16-512 (PK- 2019 PD study of Generation 2 andexanet versus Generation 1), study 16-508 (PK-PD study of andexanet in individuals of Japanese ethnicity), and study 14-505 (ANNEXA-4).

19

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

20 PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT Ondexxya 200 mg powder for solution for infusion andexanet alfa

2. STATEMENT OF ACTIVE SUBSTANCE(S) Each vial contains 200 mg of andexanet alfa.

3. LIST OF EXCIPIENTS Excipients: Tris base, Tris hydrochloride, L-arginine hydrochloride, sucrose, mannitol, polysorbate 80

4. PHARMACEUTICAL FORM AND CONTENTS Powder for solution for infusion 4 x 1 vial of 200 mg

5. METHOD AND ROUTE(S) OF ADMINISTRATION For single use only. Read the package leaflet before use. Intravenous use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE EXP

9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Alexion Europe SAS 103-105 rue Anatole France 92300 Levallois-Perret France

12. MARKETING AUTHORISATION NUMBER(S) EU/1/18/1345/001

13. BATCH NUMBER Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

21 16. INFORMATION IN BRAILLE Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC: SN: NN:

22

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Ondexxya 200 mg powder for solution for infusion andexanet alfa Intravenous use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE EXP

4. BATCH NUMBER Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 200 mg

6. OTHER Store in a refrigerator. Do not freeze. For single use only.

23

B. PACKAGE LEAFLET

24 Package Leaflet: Information for the patient and user

Ondexxya 200 mg powder for solution for infusion andexanet alfa

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully, because it contains important information for you. Please note this medicine is mainly used in emergency situations, and the doctor will have decided that you needed it. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or nurse. • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet 1. What Ondexxya is and what it is used for 2. What you need to know before you receive Ondexxya 3. How Ondexxya is used 4. Possible side effects 5. How Ondexxya is stored 6. Contents of the pack and other information

1. What Ondexxya is and what it is used for Ondexxya contains the active ingredient andexanet alfa. It reverses the effects of certain called factor Xa inhibitors (apixaban or rivaroxaban). Factor Xa inhibitors are given to prevent clots in your blood vessels. Your doctor may decide to give you Ondexxya to rapidly reverse the effects of the anticoagulant in case of a life-threatening or uncontrolled bleeding situation.

2. What you need to know before you receive Ondexxya Do not use Ondexxya: • if you are allergic to andexanet alfa or any of the other ingredients of this medicine (listed in section 6). • if you are allergic to hamster proteins • if you are receiving heparin

Warnings and precautions Reversing the effect of a factor Xa inhibitor with Ondexxya may increase the risk of blood clots. After treatment with Ondexxya, your doctor will decide when to restart anticoagulant therapy. An independent pro-coagulant effect of andexanet alfa may pose an additional risk of developing thrombosis. If you suffer side effects when you are being given Ondexxya by infusion (drip), your doctor may decide to slow down or pause your treatment. Your doctor may give you an antihistamine medicine to help with any side effects (see section 4).

If a surgery is planned for you which requires anticoagulation with heparin, Ondexxya should be

25 avoided.

Children and adolescents There is no information on the use of Ondexxya in children and adolescents.

26 Other medicines and Ondexxya Tell your doctor if you are taking, have recently taken, or might take, any other medicines. This medicine has been designed to reverse the effects of factor Xa inhibitor medicines only. It is unlikely that Ondexxya will influence the effect of other medicines or that other medicines will influence Ondexxya.

Ondexxya-treatment should be avoided if anticoagulation with heparin might become necessary. Ondexxya causes unresponsiveness to heparin.

Pregnancy and breast-feeding Tell your doctor if you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby. Ondexxya is not recommended during pregnancy or if you have the potential to become pregnant and are not using birth control. Do not breast-feed your child while you are taking this medicine. It is unknown if andexanet alfa is excreted in human milk. Driving and using machines This medicine is unlikely to affect your ability to drive and use machines.

3. How Ondexxya is used This medicine is for hospital use only. Your doctor or nurse will give you this medicine by injection or infusion into a vein. Your doctor or nurse will work out the dose of this medicine that you need. This is based on the specific anticoagulant medicine you take as well as on the dose and the time since your last dose of anticoagulant medicine. After you have received Ondexxya, your doctor will decide when to restart your anticoagulant treatment. Detailed instructions for your doctor or nurse on how to give Ondexxya are given at the end of this package leaflet (see ‘Handling instructions’). If you have any further questions on the use of this medicine, ask your doctor.

4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most common side effects associated with Ondexxya in clinical trials of healthy people were infusion–related reactions with usually mild symptoms such as flushing or feeling hot (very common side effects which may affect more than 1 in 10 people). Headache, cough, or shortness of breath (common side effects which may affect up to 1 in 10 people) happened within a few minutes to a few hours of the infusion. In clinical trials of patients with life-threatening bleeding, fever and stroke may affect up to 1 in 10 people; transient ischaemic attack (TIA), heart attack, and blood clots in the legs or lungs may affect up to 1 in 100 people (uncommon side effects).

27 List of possible side effects Very common (may affect more than 1 in 10 people) • flushing or feeling hot • effects on blood clotting markers: some markers which affect blood clotting were increased for a little while and then returned to normal. There were no blood clots in these healthy people. Common (may affect up to 1 in 10 people) • hives • dizziness • rapid or irregular heartbeat • stomach pain or discomfort • dry mouth • disturbance of taste • nausea (feeling sick) • chest discomfort • feeling cold • excessive sweating • itching • back pain • muscle spasms

Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How Ondexxya is stored This medicine will be stored in the hospital, and these instructions are intended for hospital staff only. Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the vial and the carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C to 8°C). Do not freeze. Once reconstituted, Ondexxya is for immediate use.

6. Contents of the pack and other information What Ondexxya contains • The active substance is andexanet alfa. • The other ingredients are Tris base, Tris hydrochloride, L-arginine hydrochloride, sucrose, mannitol, and polysorbate 80.

What Ondexxya looks like and contents of the pack Ondexxya is supplied in glass vials as a white to off-white powder for solution for infusion, which is reconstituted (dissolved) before use. The reconstituted solution is a clear, colourless, or slightly yellow solution.

28 Each pack contains four vials.

Marketing Authorisation Holder

Alexion Europe SAS 103-105 rue Anatole France 92300 Levallois-Perret France

Manufacturer

Alexion Pharma International Operations Unlimited Company Alexion Dublin Manufacturing Facility College Business and Technology Park Blanchardstown Rd North Dublin D15 R925 Ireland

This leaflet was last revised in . This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary.

Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu ------

The following information is intended for healthcare professionals only. Andexanet has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitor other than rivaroxaban or apixaban. Also, it will not reverse the effects of non-FXa inhibitors.

Dosage and administration Andexanet alfa is administered as an intravenous (IV) bolus at a target rate of approximately 30 mg/min over 15 (low dose) or 30 minutes (high dose), immediately followed by administration of a continuous infusion of 4 mg (low dose) or 8 mg (high dose) per minute for 120 minutes (see table 1).

29 Table 1: Dosing regimens

Initial Continuous Total number intravenous intravenous of 200 mg bolus infusion vials needed Low dose 400 mg at a target rate of 4 mg/min for 120 minutes 5 30 mg/min (480 mg) High dose 800 mg at a target rate of 8 mg/min for 120 minutes 9 30 mg/min (960 mg) Dosage recommendations have been defined from the effects of andexanet alfa in healthy volunteers administered a direct FXa inhibitor and from the ability to reverse the levels of anti- FXa activity. The posology was confirmed in a study in patients with acute major bleeding.

Reversal of apixaban The recommended dose regimen of andexanet alfa is based on the dose of apixaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of apixaban (see table 2).

Table 2: Summary of dosing for reversal of apixaban

Timing of FXa inhibitor last dose before FXa inhibitor andexanet alfa initiation FXa last dose inhibitor < 8 hours or unknown ≥ 8 hours

≤ 5 mg Low dose Apixaban Low dose > 5 mg/ High dose Unknown

Reversal of rivaroxaban The recommended dose regimen of andexanet alfa is based on the dose of rivaroxaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of rivaroxaban (see table 3).

Table 3: Summary of dosing for reversal of rivaroxaban

FXa FXa inhibitor Timing of FXa inhibitor last dose before inhibitor last dose andexanet alfa initiation

< 8 hours or unknown ≥ 8 hours

≤ 10 mg Low dose Rivaroxaban Low dose > 10 mg/ High dose Unknown

Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thromboembolic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.

30 Handling instructions Andexanet alfa is to be reconstituted and the 10 mg/mL solution then transferred without further dilution to sterile large volume syringes in case a syringe pump is used for administration or to suitable empty IV bags comprised of polyolefin (PO) or polyvinyl chloride (PVC) material. Prior to administration by IV infusion a 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein- binding filter should be used.

For reconstituted solutions, chemical and physical in-use stability have been demonstrated for at least eight hours at 25°C. From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Reconstitution Before starting reconstitution, you will need the following: • Calculated number of vials as given in table 1. • Same number of 20 mL (or larger) solvent syringes equipped with a 20 gauge (or larger) needle. • Alcohol swabs. • Large (50 mL or larger) sterile syringe. If administration is done with a syringe pump, multiple syringes should be used to contain the final volume of reconstituted product. • Intravenous bags of polyolefin (PO) or polyvinyl chloride (PVC) material (150 mL or larger) to contain the final volume of reconstituted product (if administration is done with an IV bag). • Water for injection • 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter

Andexanet alfa does not need to be brought to room temperature before reconstitution or administration to the patient. Use aseptic technique during the reconstitution procedure.

Reconstitute each vial according to the following instructions: 1. Remove the flip-top from each vial. 2. Wipe the rubber stopper of each vial with an alcohol swab. 3. Using a 20 mL (or larger) syringe and a 20 gauge (or larger) needle, withdraw 20 mL of water for injection. 4. Insert the syringe needle through the centre of the rubber stopper. 5. Push the plunger down to slowly inject the 20 mL of water for injections into the vial, directing the stream toward the inside wall of the vial to minimise foaming. 6. Gently swirl each vial until all of the powder is completely dissolved. DO NOT SHAKE the vials, as this can lead to foaming. The dissolution time for each vial is approximately three to five minutes. 7. The reconstituted solution should be inspected for particulate matter and/or discolouration prior to administration. Do not use if opaque particles or discolouration are present. 8. For the most efficient reconstitution of the needed dose, and to minimise errors, inject each vial needed with 20 mL of water for injections before proceeding to the next step. 9. Use andexanet alfa within eight hours after reconstitution when stored at room temperature.

Administration using a syringe pump 1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger) needle. 2. Prepare the bolus and infusion in separate large volume syringes. 3. Due to the additional volume, the high dose bolus and infusion will need to be

31 further separated into additional syringes (two syringes apiece for bolus and infusion). 4. To prevent the inadvertent transfer of air, be careful to hold the syringe needle up, and do not set the syringe down between multiple withdrawals from vials. 5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter, syringe pump) in preparation for administration. 6. Administer the reconstituted solution at the appropriate rate. 7. Discard all used syringes, needles, and vials, including any unused portion of reconstituted solution.

Administration using intravenous bags 1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger) needle. 2. Transfer the reconstituted solution from the syringe into appropriate IV bags. 3. Repeat steps 1 and 2 as necessary to transfer the complete volume of the bolus and the infusion into PO or PVC IV bags. 4. It is recommended that the bolus and infusion be split into two separate bags to ensure the correct administration rate. Although it is also permissible to use one PO or PVC IV bag for the bolus and infusion, the correct infusion rate must be ensured when switching from the bolus to the infusion. 5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter, IV pump) in preparation for administration. 6. Administer the reconstituted solution at the appropriate rate.

Disposal All used syringes, needles, and vials, including any unused portion of reconstituted solution, should be disposed of in accordance with local requirements.

32